During our January 10, 2011 to February 3, 2011 inspection of your pharmaceutical manufacturing facility, Lehigh Valley Technologies, Inc., located at 513 N. 12th Street, Allentown, Pennsylvania, investigator(s) from the Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.

We have reviewed your firm’s response of February, 23, 2011, and note that it lacks sufficient corrective actions. We also acknowledge your written response, dated March 9, 2011. However, because this response was received more than 15 business days after the Form FDA 483 was issued, it has not been considered.[1] We plan to evaluate this response along with any other written material provided, as a direct response to this Warning Letter.

Specific violations observed during the inspection include, but are not limited, to the following:

1. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].

For example, your firm’s Quality Control Unit (QCU) altered your acceptance criteria to approve a single (b)(4) scale-up validation lot of Oxycodone HCl 5mg tablets (i.e., lot # (b)(4)) that failed the original and approved acceptance criteria for blend uniformity. In addition, your firm failed to a collect a sufficient number of samples for both blend uniformity and dosage unit in-process samples based on a predetermined, scientifically sound, sample plan. Despite these deficiencies, your firm deemed the validation as successful and the finished product was released for distribution.

Your response is inadequate because your firm failed to provide a justification for altering your acceptance criteria to release the noted validation lot of Oxycodone HCl 5mg when an Out-of-Specification (OOS) blend uniformity result was obtained under the original acceptance criteria.

2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].

For example, your QCU approved and released a batch of Morphine Sulfate Oral Solution 20mg/ml (lot #(b)(4)) even though the bulk assay results failed the specification limits and your investigation identified several causative problems in the manufacturing process.

In addition, your QCU approved and released a batch of Morphine Sulfate Oral Solution, 20mg/ml (lot # (b)(4)) despite an initial OOS bulk assay result. These results were later confirmed through repeat testing, but further testing of additional samples produced passing results. Your QCU released the batch even though the investigation did not identify a discernable cause.

In your response, your firm states that a re-evaluation of the investigations associated with both batches concluded that the root cause was a result of any or a combination of the following: (1) sampling of the unfiltered bulk product; (2) the possibility that un-dissolved active ingredient may have been in the “T” assembly valve on the mixing tank, and/or; 3) that sample bottles collected were mislabeled. Your response, however, is inadequate because it does not address the basic failure of your quality system to exercise appropriate scientific judgment in conducting repeat testing for OOS high assay results, especially in the case of Morphine Sulfate Oral Solution 20mg/ml (lot#(b)(4)).

We acknowledge that your firm does not currently manufacture this product; however, there are still stocks of the two identified batches in the market that are within expiry and have not been evaluated.

3. Your firm has failed to establish written procedures for reprocessing batches that do not to conform to standards or specifications to ensure that the reprocessed batches conform with all established standards, specifications, and characteristics [21 C.F.R. § 211.115(a)].

For example, your firm reprocessed a lot of Oxycodone HCl Oral Solution 20mg/ml (lot #(b)(4)) when excess (b)(4) was added, although there was no established written procedure for reprocessing such batches that do not conform to standards and/or specifications.

In your response, your firm states that you have established a new Standard Operating Procedure (SOP) for reprocessing or reworking nonconforming batches of drug product. Your response, however, is inadequate because you failed to provide a rationale or any data to ensure that the reworked lot of Oxycodone HCl Oral Solution (lot #(b)(4)) met all established standards, specifications, and characteristics of a validated batch.

4. Your firm has failed to justify deviations from written production and process control procedures [21 C.F.R. § 211.100(b)].

For example, your firm failed to provide a justification for deviating from your SOP, (b)(4), entitled, “(b)(4),” that requires (b)(4). During your investigation of Oxycodone HCl 5mg capsules (lot #(b)(4)), only (b)(4) analyst conducted additional testing on the original working solution, which confirmed the initial testing, and subsequently prepared (b)(4) samples using (b)(4) capsules from the original samples. When this retesting, using a new sample preparation met specifications and the % difference criteria, the original OOS results were invalidated and the re-test results were reported.

In your response, your firm states that you have revised your SOP, (b)(4), entitled, “(b)(4),” to add a section titled, “(b)(4),” which outlines specific procedures that you believe will help address this deficiency. Your response, however, is inadequate because your firm failed to retrospectively evaluate the investigation described above in which the percent difference between the two assays were not met. In addition, both of your SOPs (i.e., (b)(4) and (b)(4)) are inadequate because neither provides clear instructions for addressing the type of deviation found with your Oxycodone HCl investigation described above. The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations.

You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.

Within fifteen (15) working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute the drug product(s) manufactured at this facility, and provide the date(s) and reason(s) you ceased production.

Your reply should be sent to the following address: U.S. Food and Drug Administration, U.S. Customhouse, Room 900, 2nd and Chestnut Sts., Philadelphia, PA 19106, Attn: Yvette Johnson, Compliance Officer.